The goals of the Unit on Cognitive Neurophysiology and Imaging (UCNI) in combining electrophysiology and fMRI techniques are two-fold. First, we aim to understand the relationship between the electrical and hemodynamic processes in the brain, since this understanding will directly impact the myriad studies using fMRI in research and clinical applications. Second, we are interested to study how activity measured from an electrode at one point in the brain covaries with activity in distant parts of the brain, as measured with fMRI, as this will provide insight into how global changes in cortical activity contribute to the response variability commonly observed during sensory processing. Under most simple stimulus conditions, electrophysiological and fMRI responses are in good agreement. For example, the presentation of a visual stimulus will elicit abrupt positive responses of both types of signals in the visual cortex, and the two signals are seen to be highly correlated. However, this agreement can break down when investigating cognitive variables, such as the direction of attention or the perceptual visibility. In previous work, for example, we demonstrated that during perceptual suppression, where a stimulus is physically present but perceptually invisible, only the fMRI signal reflected the perceptual state in the primary visual cortex. Neurons in the same area continued to fire electrical discharges to the stimulus regardless of whether or not it was perceived. This sort of discrepancy has been taken by some as an alarming sign that fMRI responses do not accurately reflect neural activity. Another viewpoint may be that the two types of signals offer a different, non-redundant, window on brain function. Following either interpretation of the discrepancy, it is clear that understanding the relationship between the two signals is of utmost importance if the two types of measurements are to be integrated into a coherent understanding of brain function. In this spirit, much of our work is in close collaboration with the neighboring Neurophysiology Imaging Facility (NIF), where trained monkeys are scanned routinely while viewing a variety of visual stimuli. The repertoire of the NIF, including simultaneous neurophysiological recordings, microinfusion, and electrical microstimulation in the magnet, offers a range of unique tools to study brain physiology related to sensation and perception. We are presently using multiple approaches to understand the relationship between neural and fMRI signals in the brain. The first approach combines functional MRI imaging with the extirpation or inactivation of neural tissue. In one project, we lesioned the primary visual cortex, which is the bottleneck of visual information reaching the visual cortex, and used fMRI to ask whether other parts of the brain would still respond to visual stimuli. We found that fMRI responses in areas beyond V1 were surprisingly intact, even though the main neural highway was no longer available. This finding suggested alternative pathways in the visual system, circumventing the primary visual cortex to reach association cortex. Present research in the lab is investigating whether the fMRI activity observed in the association areas reflects normal neural activity (the spiking of action potentials), or whether neural responses there are silent, and therefore different from the fMRI signal. Interestingly, the residual activity was completely abolished when the geniculate nucleus of the thalamus was additionally inactivated in the same animals. These multi-stage experiments, involving lesions, pharmacological inactivation, electrophysiology, and functional imaging in the same animals, are providing new insights into visual pathways in the brain, in addition to the information they offer regarding the relationship between neural and fMRI signals. We have also begun to combine electrical microstimulation inside the magnetic bore with functional imaging in awake monkeys. This technique has recently been used to infer structural and functional connectivity between areas, with functional activation far away from the site of stimulation indicating such a connection. Our preliminary results stimulating the superior colliculus have shown activation in the striate and extrastriate visual cortex. Finally, we have done extensive recordings of brain activity directly during fMRI scanning using implanted multicontact electrodes. In order to accomplish this, we steered the development of MR-compatible, implantable electrodes of two different sorts: multicontact linear arrays, and electrocorticogram electrodes. These special electrodes were constructed with special metals that produce minimal artifacts during functional scans. Following implantation of these arrays in several cortical areas, we monitored the covariation in activity between fMRI and neural signals in the brain of monkeys that were sitting alert and awake in the scanner. We found there to be a widespread correlation between the spontaneous electrical activity at a point on the brains surface and the fMRI responses throughout wide swathes of the cortex. The basis of this correlation is only now beginning to be understood, and is thought to arise from a general, coherent and global fluctuation over the brain in the resting state. This finding has potentially important implications for many researchers studying resting state functional connectivity in normal and patient populations. Specifically, the global cortical signal has traditionally been removed as an aritifact irrelevant to neural activity. Our findings suggest that this conclusion is erroneous, and that the global signal may be critical for understanding resting state brain physiology. The practical implications of large-scale signal fluctuations in the cortex, including its impact on sensory processing, is presently at the focus of our research.